The Role of Complement in Inflammatory Diseases From Behind the Scenes into the Spotlight
2007; Elsevier BV; Volume: 171; Issue: 3 Linguagem: Inglês
10.2353/ajpath.2007.070166
ISSN1525-2191
AutoresMaciej M. Markiewski, John D. Lambris,
Tópico(s)Renal Diseases and Glomerulopathies
ResumoOur understanding of the biology of the complement system has undergone a drastic metamorphosis since its original discovery. This system, which was traditionally primarily described as a “complement” to humoral immunity, is now perceived as a central constituent of innate immunity, defending the host against pathogens, coordinating various events during inflammation, and bridging innate and adaptive immune responses. Complement is an assembly of proteins found in the blood and body fluids and on cell surfaces. Soluble complement components form the proteolytic cascade, whose activation leads to the generation of complement effectors that target various cells involved in the immune response. Membrane-bound receptors and regulators transmit signals from complement effectors to target cells and limit complement activation to the surfaces of pathogens and damaged or activated host cells. The multiple interconnections among complement proteins, immune cells, and mediators provide an excellent mechanism to protect the organism against infections and support the repair of damaged tissues. However, disturbances in this “defense machinery” contribute to the pathogenesis of various diseases. The role of complement in various inflammatory disorders is multifaceted; for example, the activation of complement can significantly contribute to inflammation-mediated tissue damage, whereas inherited or acquired complement deficiencies highly favor the development of autoimmunity. Our understanding of the biology of the complement system has undergone a drastic metamorphosis since its original discovery. This system, which was traditionally primarily described as a “complement” to humoral immunity, is now perceived as a central constituent of innate immunity, defending the host against pathogens, coordinating various events during inflammation, and bridging innate and adaptive immune responses. Complement is an assembly of proteins found in the blood and body fluids and on cell surfaces. Soluble complement components form the proteolytic cascade, whose activation leads to the generation of complement effectors that target various cells involved in the immune response. Membrane-bound receptors and regulators transmit signals from complement effectors to target cells and limit complement activation to the surfaces of pathogens and damaged or activated host cells. The multiple interconnections among complement proteins, immune cells, and mediators provide an excellent mechanism to protect the organism against infections and support the repair of damaged tissues. However, disturbances in this “defense machinery” contribute to the pathogenesis of various diseases. The role of complement in various inflammatory disorders is multifaceted; for example, the activation of complement can significantly contribute to inflammation-mediated tissue damage, whereas inherited or acquired complement deficiencies highly favor the development of autoimmunity. Complement was discovered approximately 100 years ago as a heat-sensitive component of plasma that enhances the opsonization of bacteria by antibodies and facilitates antibody-dependent killing of bacteria.1Bordet J Gengou O Sur l'existences de substance sensibilisatrices dans la plupart des serum antimicrobiens. French.Ann Inst Pasteur. 1901; 15: 289-302Google Scholar The original report assigned the name “complement” to this component to reflect the idea that its function is complementary to that of humoral immunity. Thus, its very name reflects our traditional view that the complement system plays a supporting role “behind the scenes.” This terminology also corresponds to the historical concept that complement components exert their functions at the “periphery” of the defense reaction, acting exclusively as a supplement to the action of other components of the immune system. The inadequacy of this “complementary” concept becomes apparent in light of recent studies demonstrating functions of complement that are essential and “central” to the innate immune response, as well as functions that bridge innate with adaptive immunity.2Carroll MC The complement system in regulation of adaptive immunity.Nat Immunol. 2004; 5: 981-986Crossref PubMed Scopus (830) Google Scholar Today, complement should rather be viewed as a system that orchestrates and connects various responses during immune and inflammatory reactions and not merely as a killer of bacteria.3Mastellos D Lambris JD Cross-disciplinary research stirs new challenges into the study of the structure, function and systems biology of complement.in: Lambris JD Current Topics in Complement. Springer Science and Business Media, LLC, New York2006: 1-16Crossref Scopus (4) Google Scholar The complement system is composed of membrane-bound regulators and receptors as well as numerous plasma proteins that interact with various cells and mediators of the immune system.4Mastellos D Morikis D Isaacs SN Holland MC Strey CW Lambris JD Complement: structure, functions, evolution, and viral molecular mimicry.Immunol Res. 2003; 27: 367-385Crossref PubMed Scopus (51) Google Scholar These interactions vary according to the pathophysiologic context, and they occur at different steps of an immune reaction. This wide network of interactions, together with the broad range of mechanisms of complement activation, make the components of the complement system ideal candidates for coordinating events that occur as a consequence of the induction of innate immunity, as well as those that occur later during the adaptive immune reaction. This review describes the role of complement proteins in the regulation and synchronization of an acute inflammatory reaction, which aims to eliminate pathogens and clear damaged host cells and proceeds with obvious benefit for the host. In addition, we discuss the contribution of complement to the pathophysiology of selected diseases. Unfortunately, several associations of complement with other immune mediators or cells that contribute to the successful battle against microbes or facilitate the clearance and repair of damaged host tissues can paradoxically become responsible for various pathologies when control mechanisms fail or the immune system encounters unusual stimulatory factors. In some pathophysiologic situations, an excess of complement is deleterious to the host, whereas under other circumstances a total lack or deficiency of complement contributes to the development of disease. These two aspects of complement pathophysiology will also be discussed. The complement system actively regulates various steps of an inflammatory response. Inflammation is currently viewed as a complex pathophysiologic process that engages literally hundreds of mediators and different cell types and tissues and can be initiated by any stimulus causing cell injury. Often, inflammation is a response to infection. However, chemical or physical injury alone can also induce this reaction.5Nathan C Points of control in inflammation.Nature. 2002; 420: 846-852Crossref PubMed Scopus (2109) Google Scholar The ultimate goal of this process is to eliminate the causative agent with minimal destruction to host tissues and to repair the damage caused by the initiating factor. The duration of an inflammatory response depends in part on whether a successful resolution and neutralization of the initiating agent has occurred. Acute inflammation is a relatively short process, lasting from minutes to a few days, and its main characteristics are an exudation of fluid and plasma proteins and an emigration of leukocytes into an extravascular compartment. These vascular and cellular responses are mediated by chemical factors derived from plasma or cells and are responsible for the classic clinical signs of inflammation, originally described by Aulus Cornelius Celsus and later modified by Rudolph Virchow: tumor (swelling), rubor (redness), dolor (pain), calor (warmth), and functio laesa (loss of function). If the acute response is unable to remove the causative factor or repair the damage at the site of inflammation, a chronic process, in which tissue destruction and repair occur while the inflammatory reaction continues, may develop. Chronic inflammation can also result from stimuli that initiate a low-grade and asymptomatic response.6Collins T Acute and chronic inflammation.in: Cotran RS Kumar V Collins T Pathologic Basis of Disease. W.B. Saunders, Philadelphia1999: 50-88Google Scholar Although an inflammatory reaction can occur in any tissue exposed to an injurious stimulus, the hallmark of this process is the response of vascularized connective tissue.6Collins T Acute and chronic inflammation.in: Cotran RS Kumar V Collins T Pathologic Basis of Disease. W.B. Saunders, Philadelphia1999: 50-88Google Scholar The first changes observed during inflammation are alterations in the vascular flow and changes in the caliber of small blood vessels. Vasodilation of arterioles, resulting in the opening of new capillary beds in the area of injury, follows transient vasoconstriction, which lasts only seconds. Larger arterioles and newly opened capillary vessels increase the blood flow to this area. Gradually, progressive changes in the endothelium enhance the vascular permeability of the microvasculature, leading to the escape of the fluid into an extravascular compartment. The decrease in the amount of the fluid in the lumen of blood vessels enhances the viscosity of the blood and slows down the flow rate. As a result of these alterations in blood flow, the margination of leukocytes begins. Over time, leukocytes stick to the endothelium, at first transiently (rolling), then more avidly (adhesion), and soon afterward, they migrate through the vascular wall (transmigration) into the interstitial tissue. At this point, the essential goal of acute inflammation, to bring leukocytes and plasma mediators to site of injury, is achieved.6Collins T Acute and chronic inflammation.in: Cotran RS Kumar V Collins T Pathologic Basis of Disease. W.B. Saunders, Philadelphia1999: 50-88Google Scholar Efficient, rapid, and occurring in synchrony with the initiation of an inflammatory reaction, the activation of complement is a prerequisite for its involvement in regulation of inflammatory processes. The mechanisms that govern this activation are well defined and understood mainly in terms of the reactions occurring in the intravascular space. However, the soluble components of complement are present not only in the circulation but also in body fluids and tissues, ready to engage in defense reactions triggered by exogenous (eg, infectious agents) or endogenous (eg, ischemia, autoimmunity) stimuli that could cause cell injury.7Janeway Jr, CA Travers P Walport M Shlomchik MJ Innate immunity. Immunobiology. Garland Publishing, New York2005: 37-100Google Scholar In addition to the specific activation induced by antigen-antibody complexes, complement is activated through the pattern recognition receptors, which have the ability to discriminate between self and non-self antigens based on repeating patterns of molecular structure (pathogen-associated molecular patterns) present on the surface of pathogens.8Kohl J Self, non-self, and danger: a complementary view.in: Lambris JD Current Topics in Complement. Springer Science and Business Media, LLC, New York2006: 71-94Crossref Scopus (79) Google Scholar Complement-activating pattern recognition receptors include mannose-binding lectin (MBL), ficolins, C-reactive protein, C1q, and natural IgM (IgM). These molecules share many common properties with Toll-like receptors, which often initiate an innate immune response and also belong to the category of pattern recognition receptors.8Kohl J Self, non-self, and danger: a complementary view.in: Lambris JD Current Topics in Complement. Springer Science and Business Media, LLC, New York2006: 71-94Crossref Scopus (79) Google Scholar The contribution of the pattern recognition system to complement activation assures the rapid initiation of the complement cascade as a part of an early immune response and inflammation. In fact, the activation of complement occurs immediately with high efficiency when the system encounters appropriate stimuli. For example, in infection induced by Leishmania, approximately 90% of promastigotes are lysed by complement in just 2.5 minutes after contact with human blood.9Domínguez M Moreno I Aizpurua C Torano A Early mechanisms of Leishmania infection in human blood.Microbes Infect. 2003; 5: 507-513Crossref PubMed Scopus (22) Google Scholar Therefore, complement effectors generated as a result of this activation can participate in the earliest events of an inflammatory reaction.7Janeway Jr, CA Travers P Walport M Shlomchik MJ Innate immunity. Immunobiology. Garland Publishing, New York2005: 37-100Google Scholar Complement is activated through the classical, lectin, or alternative pathways (Figure 1). The classical pathway is initiated by antibodies produced during the humoral response, by natural antibodies, and by other molecules that are generated as a result of an inflammatory reaction such as C-reactive protein or serum amyloid protein. The binding of C1q to antigen-antibody complexes initiates the proteolytic cleavage of complement components in the classical pathway. The lectin pathway begins with the recognition and binding of pathogen-associated molecular patterns by lectin proteins, including MBL. C1q and MBL are structurally similar molecules, and both the classical and lectin pathways require C2 and C4 complement components for the generation of the C3 convertase. The alternative pathway differs significantly from the classical and lectin pathways because it is initiated by the spontaneous hydrolysis of C3, leading to the formation of C3(H2O) and the binding of a small amount of C3b to hydroxyl groups on cell surface carbohydrates and proteins. C3(H2O) forms a complex with factor B, followed by the cleavage of factor B within this complex by factor D. The final product of these enzymatic reactions is the C3(H2O)Bb complex. Once deposited on the surface of cells or pathogens, C3b binds more factor B, and this binding gradually amplifies the activation cascade. All three pathways of complement activation lead to the formation of C3 convertases that cleave C3 to C3a and C3b. C3b contributes to the formation of the C5 convertase, which in turn cleaves C5 to C5a and C5b. Complement anaphylatoxins C3a, C4a, and C5a are potent inflammatory mediators, and C5b initiates the formation of C5b-9 terminal complement complex, which is incorporated into bacterial cell walls and induces the lysis of pathogens, in particular gram-negative Neisseria strains.10Walport MJ Complement: first of two parts.N Engl J Med. 2001; 344: 1058-1066Crossref PubMed Scopus (2476) Google Scholar The activity of the anaphylatoxins is regulated by carboxypeptidases, including carboxypeptidase N, which circulate in the plasma or are present in the tissues. Carboxypeptidase N hydrolyzes the carboxy-terminal peptide bond of anaphylatoxins, releasing the carboxy-terminal arginine. These derivatives of anaphylatoxins are known as C3a-desArg and C5a-desArg. C3a, C3a-desArg, and C4a exhibit direct antibacterial properties;11Pasupuleti M Walse B Nordahl EA Morgelin M Malmsten M Schmidtchen A Preservation of antimicrobial properties of complement peptide C3a, from invertebrates to humans.J Biol Chem. 2007; 282: 2520-2528Crossref PubMed Scopus (60) Google Scholar however, some of the biological activities of the desArg forms of C3a and C5a are significantly reduced (by 10- to 100-fold) when compared with those of their full-length forms.12Matthews KW Mueller-Ortiz SL Wetsel RA Carboxypeptidase N: a pleiotropic regulator of inflammation.Mol Immunol. 2004; 40: 785-793Crossref PubMed Scopus (136) Google Scholar C3 and C5 can also be cleaved locally at sites of ongoing inflammatory reactions without the participation of other complement components (Figure 1). Several proteolytic enzymes present within inflammatory exudates, such as lysosomal enzymes or elastase released from neutrophils,13Vogt W Damerau B Luhmann B Hesse D Haller Y Complement activation in human lymph: modulation by the contact activation system and by leukocytes.Int Arch Allergy Appl Immunol. 1986; 79: 423-433Crossref PubMed Scopus (18) Google Scholar have been shown to activate C3 and C5. Kallikrein, a component of the kinin and fibrinolysis systems, has the ability to cleave C5 and release C5a.14Wiggins RC Giclas PC Henson PM Chemotactic activity generated from the fifth component of complement by plasma kallikrein of the rabbit.J Exp Med. 1981; 153: 1391-1404Crossref PubMed Scopus (73) Google Scholar Recent work has shown that C5a can be generated in mice lacking C3 through the proteolytic cleavage of C5 by thrombin.15Huber-Lang M Sarma JV Zetoune FS Rittirsch D Neff TA McGuire SR Lambris JD Warner RL Flierl MA Hoesel LM Gebhard F Younger JG Drouin SM Wetsel RA Ward PA Generation of C5a in the absence of C3: a new complement activation pathway.Nat Med. 2006; 12: 682-687Crossref PubMed Scopus (798) Google Scholar These cleavage reactions result in the generation of active complement components that have proinflammatory properties such as anaphylatoxins as well as C3b or C5b. C3b might contribute to the formation of the alternative pathway convertase. Therefore, complement activation initiated by noncomplement proteins might be amplified through the alternative pathway. We have categorized the mechanisms, initiating complement activation by noncomplement proteins into a separate pathway, and named it here as the extrinsic protease pathway of complement activation (Figure 1). Thus, a large variety of mechanisms and pathways involved in complement activation ensure that active complement components can potentially be generated at almost every step of both innate and adaptive immune responses. Complement components that are activated in plasma and body fluids are engaged in the regulation of virtually all phases of an acute inflammatory reaction, including changes in vascular flow and caliber, the increase in vascular permeability, extravasation of leukocytes, and chemotaxis. Several regulatory functions of complement affect other inflammatory mediators, whereas other complement activities are associated with the direct action of complement proteins on target cells. Because of its variety of activating mechanisms, complement can independently participate in the regulation of inflammation, in either the presence or absence of an infection. Tissue injury, the primary signal for launching the innate immune response and inflammation, initiates several signaling cascades that regulate changes in the microvasculature, including the activation of complement. Damaged cells release a number of constitutively expressed proteins, such as heat shock proteins,16Basu S Binder RJ Suto R Anderson KM Srivastava PK Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-κB pathway.Int Immunol. 2000; 12: 1539-1546Crossref PubMed Scopus (1099) Google Scholar the transcription factor HMGB1 (for the high mobility group),17Scaffidi P Misteli T Bianchi ME Release of chromatin protein HMGB1 by necrotic cells triggers inflammation.Nature. 2002; 418: 191-195Crossref PubMed Scopus (3467) Google Scholar and mitochondrial peptides bearing the N-formyl group that are characteristic of prokaryotic proteins.17Scaffidi P Misteli T Bianchi ME Release of chromatin protein HMGB1 by necrotic cells triggers inflammation.Nature. 2002; 418: 191-195Crossref PubMed Scopus (3467) Google Scholar It is interesting that heat shock proteins can activate the complement system in both an antibody-dependent and -independent manner.18Prohászka Z Singh M Nagy K Kiss E Lakos G Duba J Fust G Heat shock protein 70 is a potent activator of the human complement system.Cell Stress Chaperones. 2002; 7: 17-22Crossref PubMed Scopus (89) Google Scholar The complement activation initiated by heat shock proteins can occur in the absence of pathogens. Therefore, even aseptic tissue injury activates the complement cascade. In addition, microbes and their shed or secreted products activate complement through binding to C1q or MBL.4Mastellos D Morikis D Isaacs SN Holland MC Strey CW Lambris JD Complement: structure, functions, evolution, and viral molecular mimicry.Immunol Res. 2003; 27: 367-385Crossref PubMed Scopus (51) Google Scholar Anaphylatoxins generated through complement activation interact with their receptors expressed on various cells, thereby modulating their inflammatory properties. Mast cells are widely distributed in the connective tissue around blood vessels and are among the first responders during inflammation.19Lee DM Friend DS Gurish MF Benoist C Mathis D Brenner MB Mast cells: a cellular link between autoantibodies and inflammatory arthritis.Science. 2002; 297: 1689-1692Crossref PubMed Scopus (682) Google Scholar During their response to activation by anaphylatoxins, mast cells release histamine, preformed tumor necrosis factor (TNF)-α, newly synthesized cytokines, tryptases, other proteases, and chemokines. In addition, C5a activates the lipoxygenase pathway of arachidonic acid metabolism in neutrophils and monocytes, leading to an acceleration of eicosanoid production by these cells.20Clancy RM Dahinden CA Hugli TE Complement-mediated arachidonate metabolism.Prog Biochem Pharmacol. 1985; 20: 120-131PubMed Google Scholar Mast cells and neutrophils that are activated by complement anaphylatoxins release mediators that cause vasodilation and extravasation of fluid.19Lee DM Friend DS Gurish MF Benoist C Mathis D Brenner MB Mast cells: a cellular link between autoantibodies and inflammatory arthritis.Science. 2002; 297: 1689-1692Crossref PubMed Scopus (682) Google Scholar Another cell population that is activated at the very beginning of the inflammatory reaction are the macrophages, which are found in large numbers in connective tissue, the submucosal layer of the gastrointestinal tract, the lung, the liver, and the spleen.7Janeway Jr, CA Travers P Walport M Shlomchik MJ Innate immunity. Immunobiology. Garland Publishing, New York2005: 37-100Google Scholar Although the migration of neutrophils to tissue is viewed as a hallmark of acute inflammation, macrophages are among the first cells to recognize pathogens that cross the epithelial barrier and begin to replicate in the host tissue.7Janeway Jr, CA Travers P Walport M Shlomchik MJ Innate immunity. Immunobiology. Garland Publishing, New York2005: 37-100Google Scholar The recognition of foreign antigens occurs through the pattern recognition receptors expressed by these cells; therefore, macrophages can immediately respond to infection. Macrophages also express receptors for anaphylatoxins, which deliver additional activation signals to these cells. This activation leads to the secretion of cytokines and chemokines by macrophages. C5a has the capacity to induce gene expression and protein synthesis of TNF-α and interleukin (IL)-1β in monocytes and macrophages.21Schindler R Gelfand JA Dinarello CA Recombinant C5a stimulates transcription rather than translation of interleukin-1 (IL-1) and tumor necrosis factor: translational signal provided by lipopolysaccharide or IL-1 itself.Blood. 1990; 76: 1631-1638Crossref PubMed Google Scholar Although the role of C3a in the modulation of TNF-α and IL-1β production and release is not as well characterized as that for C5a, it has been shown that C3a and C3a-desArg may stimulate the production of these cytokines.22Takabayashi T Vannier E Clark BD Margolis NH Dinarello CA Burke JF Gelfand JA A new biologic role for C3a and C3a desArg: regulation of TNF-α and IL-1β synthesis.J Immunol. 1996; 156: 3455-3460PubMed Google Scholar C3a signaling seems to be costimulatory with lipopolysaccharide signaling and, depending on the pathophysiologic background and target cell population, it has a stimulatory or an inhibitory effect.22Takabayashi T Vannier E Clark BD Margolis NH Dinarello CA Burke JF Gelfand JA A new biologic role for C3a and C3a desArg: regulation of TNF-α and IL-1β synthesis.J Immunol. 1996; 156: 3455-3460PubMed Google Scholar C3a also increases the expression of IL-6 when acting as a costimulator of lipopolysaccharide signaling.23Fischer WH Jagels MA Hugli TE Regulation of IL-6 synthesis in human peripheral blood mononuclear cells by C3a and C3a(desArg).J Immunol. 1999; 162: 453-459PubMed Google Scholar The signals controlling TNF-α and IL-1β secretion seem to be especially important for the course of the acute inflammatory response, because these cytokines have a significant influence on local (ie, at the site of injury) and peripheral homeostasis. These two cytokines share many properties, such as the capacity to activate the endothelium, leukocytes, and fibroblasts.24Dinarello CA Biologic basis for interleukin-1 in disease.Blood. 1996; 87: 2095-2147Crossref PubMed Google Scholar, 25Beutler B TNF, immunity and inflammatory disease: lessons of the past decade.J Investig Med. 1995; 43: 227-235PubMed Google Scholar In the endothelium, TNF-α and IL-1β induce a spectrum of changes, mostly regulated at the transcription level, that are referred to as endothelial activation. These changes include the synthesis of endothelial adhesion molecules, other cytokines, chemokines, growth factors, eicosanoids, nitric oxide, and enzymes associated with matrix remodeling.26Pober JS Cotran RS The role of endothelial cells in inflammation.Transplantation. 1990; 50: 537-544Crossref PubMed Scopus (756) Google Scholar In addition, TNF-α and Il-1β increase the surface thrombogenicity of the endothelium.27Bevilacqua MP Endothelial-leukocyte adhesion molecules.Annu Rev Immunol. 1993; 11: 767-804Crossref PubMed Scopus (1281) Google Scholar TNF-α causes aggregation and priming of neutrophils, leading to augmented responses of these cells to other mediators. TNF-α also induces the release of proteolytic enzymes from mesenchymal cells, thus contributing to tissue damage.24Dinarello CA Biologic basis for interleukin-1 in disease.Blood. 1996; 87: 2095-2147Crossref PubMed Google Scholar, 25Beutler B TNF, immunity and inflammatory disease: lessons of the past decade.J Investig Med. 1995; 43: 227-235PubMed Google Scholar The interactions between the complement system and proinflammatory cytokines are reciprocal. Several reports have suggested that proinflammatory cytokines enhance the expression of anaphylatoxin receptors in inflammatory cells.28Burg M Martin U Rheinheimer C Kohl J Bautsch W Bottger EC Klos A IFN-γ up-regulates the human C5a receptor (CD88) in myeloblastic U937 cells and related cell lines.J Immunol. 1995; 155: 4419-4426PubMed Google Scholar, 29Mäck C Jungermann K Gotze O Schieferdecker HL Anaphylatoxin C5a actions in rat liver: synergistic enhancement by C5a of lipopolysaccharide-dependent α(2)-macroglobulin gene expression in hepatocytes via IL-6 release from Kupffer cells.J Immunol. 2001; 167: 3972-3979Crossref PubMed Scopus (33) Google Scholar It also seems that the effect of anaphylatoxins on cytokine expression depends strictly on the pathophysiological context of the ongoing inflammatory response. For example, in sepsis, excessive C5a generation leads to up-regulation of IκBα (nuclear factor κB inhibitor) in neutrophils, consequently decreasing nuclear factor κB transcriptional activity and inhibiting lipopolysaccharide-mediated stimulation of TNF-α production.30Riedemann NC Guo RF Bernacki KD Reuben JS Laudes IJ Neff TA Gao H Speyer C Sarma VJ Zetoune FS Ward PA Regulation by C5a of neutrophil activation during sepsis.Immunity. 2003; 19: 193-202Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar Changes in the caliber of the arterioles and blood flow alterations are associated with the increased vascular permeability induced by changes in the endothelium. The hemodynamic changes and the increased permeability of the endothelial barrier lead to the formation of an inflammatory exudate, which contains protein-rich fluid and inflammatory cells. Formation of inflammatory exudates permits inflammatory mediators and cells to accumulate at the sites of injury and to efficiently fight invading pathogens or eliminate other inflammation-causing factors. Increased vascular permeability is caused by functional and structural changes in the endothelial barrier. These include the formation of endothelial gaps in venules, reorganization of the endothelial cytoskeleton, increased transcytosis across the endothelial cytoplasm, direct and leukocyte-mediated endothelial injury, delayed prolonged leakage (illustrated by sunburn), and leakage from blood vessels newly formed during angiogenesis.31Bacon PA Endothelial cell dysfunction in systemic vasculitis: new developments and therapeutic prospects.Curr Opin Rheumatol. 2005; 17: 49-55Crossref PubMed Scopus (68) Google Scholar Many of these endothelial alterations are mediated by factors already discussed here, including histamine, kinins, leukotrienes, and TNF-α.31Bacon PA Endothelial cell dysfunction in systemic vasculitis: new developments and therapeutic prospects.Curr Opin Rheumatol. 2005; 17: 49-55Crossref PubMed Scopus (68) Google Scholar The expression and release of these mediators is controlled, at least in part, by anaphylatoxins. Intriguingly, C5a can also be involved in angiogenesis, which is an essential process involved in tissue repair after injury. C5a-stimulated human umbilical vein endothelial cells exhibit an increased expression of genes involved in endothelial adhesion, migration, and angiogenesis.32Albrecht EA Chinnaiyan AM Varambally S Kumar-Sinha C Barrette TR Sarma JV Ward PA C5a-induced gene expression
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